In 2008, leading infectious diseases physician scientists representing Infectious Diseases Society of America published a report titled "The Epidemic of Antibiotic-Resistant Infection" in which they declared "We are in the midst of an emerging crisis of antibiotic resistance for microbial pathogens in the United States and throughout the world." It is widely accepted that the only means to effectively combat the widespread evolution of bacterial pathogens to resist existing drugs is to innovate new drugs that inhibit novel targets. The peptidoglycan (PG) layer is considered the Achilles'Heel of bacteria and the drugs that inhibit the final step of its synthesis, namely the ?-lactams, represen ~60% of all antibiotics in clinical use and therefore have the highest impact in treating bacterial infections in humans. The final step of the PG biosynthesis is catalyzed by 3,3- and 4,3-transeptidases. The ?-lactams act by inhibiting 4,3-transpeptidases. However, there are no known agents that specifically inhibit 3,3-transpeptidases. We have shown that 3,3-transpeptidases are essential for M. tuberculosis to grow and cause disease and therefore comprise novel target for drug development. Can inhibiting this novel target usher us, once again, to a new era of effective antibacterial drugs? In this proposal we present the rationale, preliminary data, demonstrate that 3,3-transpeptidase is a novel target with the promise of a high-impact in treatment of bacterial infections and propose studies to achieve these goals. We and others have recently shown that carbapenems, a class of ?-lactam drugs, binds and inhibits 3,3-transpeptidases. In this proposal we will test the hypothesis that variants based on the carbapenem structure can inhibit 3,3-transpeptidase activity and consequently kill M. tuberculosis. By focusing on 3,3- transpeptidase activity, an unexploited but validated drug target, we expect to develop new carbapenems that have activity against drug sensitive and resistant strains of M. tuberculosis.
There are numerous bacteria commonly labeled as 'superbugs'or 'bad bugs'that are resistant to existing drugs. Infections by these superbugs are increasing at an alarming rate in the US and around the world. We propose to redesign and develop a novel carbapenem drug, a class of drug that has a long history of successful use in humans, for treatment of infections with drug resistant bacteria.